1, 4-benzodiazepines



United States Patent Ofi ice 3,244,698 i atented Apr. 5, 1966 3,244,693L4-EENZGDEAZEPTNES Milan Radoje Usliokovic, Montclair, and Wilhelm Wen=ner, Upper Montclair, N.J., assignors to Hoiimanmha Roche EEC. Nut'ley,NJ, a corporation of New .Fersey No Drawing. Original application Get.4, 1962, Ser. No. 228,256. Divided and this application July 27, 19%,Ser. No. 475,270

4 Claims. (Cl. Mil-239) The following application is a division ofapplication Serial No. 228,256, filed October 4, 1962.

This invention relates to novel fused heterocyclic ring compounds, aswell as novel intermediates used in their preparation and methods fortheir preparation. More particularly, the novel compounds of thisinvention are reduction products of 3H-l,4-benZod-iazepine-2,5(1H,4H)-diones. Specifically, the novel reduction products of this invention are11-1-2,3-dihydro-1,4-benzodiazepines of the forumla:

l a N--CH2 R4 CHR2 CH=N and 1H-2,3,4,5-tetrahydro-1,4-benzodiazepines ofthe formula:

wherein R is selected from the group consisting of hydrogen, loweralkyl, aryl-lower alkyl, nitroaryl-lower alkyl and cyclo-loweralkyl-lower alkyl; R and R are each selected from the group consistingof hydrogen and lower alkyl; and R is selected from the group consistingof hydrogen and halogen.

The compounds of the invention above form acid addition salts with bothorganic and inorganic acids, and such acid addition salts are within thescope of the present invention. More specifically, they formpharmaceutically acceptable acid addition salts with medicinallyacceptable acids, both organic and inorganic, such as, for example,hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid,sulfuric acid, carbonic acid, acetic acid, formic acid, succinic acid,maleic acid, methanesulfonic acid, toluenesulfonic acid, and the like.

As used in this description, the terms lower alkyl includes bothstraight and branched chain saturated hydrocarbon groups such as methyl,ethyl, propyl, isopropyl, butyl, and the like. In the terms aryl-loweralkyl, nitroaryl-lower alkyl and cyclo-lower alkyl-lower alkyl, thelower alkyl group is of the same character. Thus, for example, the termaryl-lower alkyl includes groups such as benzyl and the termnitroaryl-lower alkyl includes groups such as nitrobenzyl. Moreover, theterm cyclolower alkyl-lower alkyl includes groups such ascyclohexylmethyl. The term halogen includes all four halogens.

Compounds of this invention can be prepared by a variety of methods. Inone embodiment, an appropriate anthranilic acid or anthranilic acidlower alkyl ester is reacted with an a-halo-lower alkanoyl halide toform an intermediate of the formula wherein R R and R have the samemeaning as above; R is selected from the group consisting of hydrogenand lower al'kyl; and X is halogen.

These intermediates of Formula III are novel compounds and are withinthe scope of the instant invention. It should be noted that when ananthranilic acid is used as a starting material yielding as the producta compound of Formula III wherein R is hydrogen, that said product canbe esterified to yield a compound of Formula III wherein R is loweralkyl. Also, the halogen represented by X can be any halogen, butbromine is preferred. In a second step of the reaction sequence thecompound of Formula III above is reacted with a compound of the formula:

R -NH wherein R has the same meaning as above.

wherein R R R and R have the same meaning as above.

In another embodiment of the invention an appropriate o-nitrobenzoicacid or lower alkyl ester thereof can be reacted with a lower alkylester of an a-amino acid to form a corresponding o-nitrohippuric acidlower alkyl ester, which can then be reduced to form the correspondingo-aminohi-ppuric acid lower alkyl ester. This in turn can be reactedwith piperidine to form the corresponding o-aminohippuric acidpiperidide. The piperidide can then be hydrolyzed resulting in formationof the appropriate compound of Formula V above.

The compounds of Formulas I and 11 above can be formed from compounds ofFormula V by hydrogenation in the presence of a suitable hydrogenationcatalyst, or by use of a suitable reducing agent such as, for example,lithium aluminum hydride.

Compounds of Formulas 11, Hi and V wherein R and/ or R is hydrogen canbe converted into compounds wherein R and/or R is other than hydrogen byconventional means. For example, compounds wherein R and/ or R ishydrogen can be alkylated with conventional alkyla-ting agents such as,for example, lower alkyl halides. Also compounds wherein R is hydrogencan be aryl-alkylated, for example, benzyiated. Moreover, compounds.

of Formula V wherein R is aryl-lower alkyl can be selectivelyhydrogenated to obtain compounds of Formula I wherein R is, for example,cyclohexyl-lower alkyl. This hydrogenation can be effected in thepresence of a suitable catalyst, for example, in the presence ofpalladium/ carbon.

The compounds of Formulas I-Il above and their pharrnaceuticaliyacceptable acid addition salts are useful as anticonvulsants. They canbe administered internally, for example, orally or parenterally, withdosage adjusted to individual reqiurements, in conventionalpharmaceutical formulations, both solid and liquid, such as capsules,tablets, dragees, suppositories, suspensions, emulsions and the like.The compounds can, if desired, be in mixture with standardpharmaceutical carriers or adjuvants; and, if desired, other activeingredients.

The following examples are illustrative but not limitative of theinvention. All temperatures are stated in degrees centigrade.

Example 1 To a stirred solution of 25 g. of N-methylanthranilic acidmethyl ester and 13 ml. of pyridine in 1500 ml. of dry ether at 30.6 g.of bromoacetyl bromide was added dropwise, and stirring continued for 2hours. The resulting suspension was filtered, and the filtrateevaporated. The residue was recrystallized from ether, yielding N-bromoacetyl-N-methylanthranilic acid methyl ester, M.P. 80-82".

Example 2 A solution of 2 g. of N-bromoacetyl-N-methylanthranilic acidmethyl ester in 500 ml. of methanol was saturated with ammonia gas. Thetemperature rose to the boiling point and the solution was left standingovernight at room temperature. After evaporation to dryness, water wasadded and the mixture extracted with methylene chloride. The extract waswashed with water, dried and evaporated, The crystalline residue,recrystallized rom acetone, yielded 1-methyl-3H-1,4-benzodiazepine-2,5(1H,4H)-dione, M.P. 190191.5.

Example 3 To a solution of 25 g. of ethyl o-nitrohippurate in 1' literof methanol, there was added 2.5 g. of Pd/C catalyst, and the mixturehydrogenated at room temperature and normal pressure. After 3mole-equivalents of hydrogen were absorbed, the reaction stopped. Thecatalyst was filtered oil and the solution evaporated, givingcrystalline ethyl o-aminohippurate, M.P. 152-153.

Example 5 A solution of g. of ethyl o-aminohippurate in 100 ml. ofmethanol and 100 ml. of piperidine was refluxed for 24 hours. Afterevaporation in vacuo, the sirupy residue was crystallized from acetone,giving o-aminohippuric acid piperidide, M.P. 125-126.

Example 6 A solution of 13 g. of o-aminohippuric acid piperidide in 200ml. of glacial acetic acid was refluxed for 4 hours. Upon addition oi200 ml. of water, 3H-l,4-benzodiaze pine-2,5(1H,4H)-dionc precipitatedand was isolated by filtration, M.P. 327328.5.

4 Example 7 A solution of 20 g. of N-benzylanthranilic acid in 500 ml.of methanol saturated with hydrogen chloride was reflux d for 3 hours.poured on ice, made alkaline with 3 N sodium hydroxide, extracted withmethylene chloride, washed, dried and evaporated, yieldingN-benzylanthranilic acid methyl ester.

To a solution of 12.6 g. of N-benzylanthranilic acid methyl ester and4.2 g. of pyridine in 500 ml. of ether, 10.6 g. of bromoacetyl bromidewas added dropwise with stirring. The resulting suspension was stirredfor an additional 2 hours, filtered and evaporated. The green sirupyN-bromoacetyl-N-benzylan thranilic acid methyl ester so obtained wasdissolved in 1 liter of methanol, and the solution then saturated atroom temperature with ammonia. After 8 hours, the reaction mixture wasevaporated and the residue crystallized from methylene chloride-ether,giving 1 benzyl'3H-1,4-benzodiazepin-2,5(1H,4-H)-dione, M.P. 183-184".

Example 8 To a solution of 3 g. of 1-benzyl-3H,1,4-benzodiazepiniExample 9 5.25 g. of 3H-l,4-benzodiazepin-2,5(1H,4H)-dione was added toa solution of 750 mg. of sodium in 200 ml. of methanol, followed byaddition of 200 ml. of dimethylformamide. The mixture was thenevaporated in vacuum to dryness, the residue was dissolved in ml. ofdimethylform'amide, and after the addition of 20 ml. of methyl iodide,the reaction mixture was stirred for two hours. Water was then added,and the excess of methyl iodide was evaporated off in vacuo. Theresulting mixture was extracted with methylene chloride, the extractwashed with water, dried and evaporated. The noncrystalline residue waschromatographed on alumina. The fractions with benzene were crystallizedfrom acetone-ether, and gave 1,4 dimethyl 31-11,4-benzodiazepin-2,5(1H,4H)- dione, M.P. 148.5151.5.

The fractions with 5% ethylacetate-benzene were crystallized fromacetone, and gave 1-met'hyl-3H,l,4-benzodiazepin-2,5 (1H,4H)-dione, M.P.194-197".

The products so obtained showed no depression of melting point whenmixed with the same products prepared by the methods of Examples. 3 and2 above, respectively.

Example 10 The sirupy N-benzyl-N-bromoacetylanthranilic acid methylester, obtained from 12 g. of N-benzylanthranilic acid methyl ester bythe method of Example 7 above, was dissolved in 1000 ml. of methanol,and the solution saturated with gaseous methylamine, whereupon thetemperature rose to boiling. The mixture was left standing overnight atroom temperature, then evaporated, diluted with water, and extractedwith methylene chloride. The extract was washed with water, dried andevaporated. The residue crystallized from acetone-ether, and gave 1-benzyl 4 methyl 3H 1,4 benzodiazepin 2,5- (1H,4H)-dione, M.P. -151.

Example 11 To a stirred solution of 15 g. of methyl anthranilate and 8g. of pyridine in 500 ml. of anhydrous ether at 0, 20 g. of bromoacetylbromide was added dropwise. Stirring was continued for two hours at:room temperature. The solution was then filtered and evaporated, andthe The reaction mixture was then residue recrystallized from hexane,giving N-bromoacetylanthranilic acid methyl ester, M.P. 8687.

Into a solution of 20 g. of N-bromoacetylanthranilic acid methyl esterin 1500 ml. of methanol, gaseous methylamine was introduced for hours at60, and then the solution was evaporated. Water was added and theresulting mixture extracted with methylene chloride, the extract washedwith water, dried and evaporated. Crystallization from acetone-ether,gave 4-methyl-3H-1,4-benzodiazepin-2,5(1H,4H)-dionc, M.P. 2484252".

Example 1 2 To a solution of 5.5 g, of N-bromoacetylanthranilic acidmethyl ester in 200 ml. of acetone, 4 g. of potassium iodide was addedand the reaction mixture stirred at room temperature for two hours.After dilution with a large excess of water, the precipitate wasfiltered off, washed with water and dried. It gaveN-iodoacetylanthranilic acid methyl ester, M.P. 86-89.

' To a solution of 4.7 g. of N-iodoacetylanthranilic acid methyl esterin 120 ml. of methanol, 5.5 ml. of a methanolic solution containing0.915 g. of methylamine (2 mole equivalents) was added. The mixture wasleft 2 days at room temperature, then refluxed 4 hours and evaporated. Alarge excess of water was added to the residue, the mixture was madeacidic with acetic acid and extracted with methylene chloride. Theextract was washed with water, dried and evaporated. The crystallineresidue was boiled with ether, giving N-methylaminoacetylanthranilicacid methyl ester, M.P. 130-131.5.

2.8 g. of N-methylaminoacetylanthranilic acid methyl ester was heatedfor one hour at 160 under vacuum. After cooling, the product wascrystallized from acetone, giving4-methyl-3H-1,4-benzodiazepin-2,5(1H,4H)-dione, M.P. 248252, infraredspectrum and mixed melting point show the product to be identical withthe one obtained in Example 11 above.

Example '13 To a solution of 13.7 g. of anthranilic acid in 200 ml. ofdimethylforrnamide, 20.2 g. of bromoacetyl bromide was added. Themixture was stirred for two hours, then diluted with water, theresultant crystals filtered off and dried; yieldingNbromoacetylanthranilic acid, M.P. 165 5172".

To a solution of 18 g. of N-bromoacetylanthranilic acid in 200 ml..ofmethanol, 200 ml. of N methylamine in methanol was added. The mixturewas left at room temperature for one week, then evaporated and theresidue heated two hours at 190-200". After cooling, water was added andthe resultant mixture extracted in methylene chloride; and the extractdried and evaporated. The prodnot was crystallized from acetone, giving4-methyl-3H-1,4- benzodiazepin-2,5(1H,4H)-dione, M.P. 246250. Infraredspectrum and mixed melting point show the prodnet to be identical withthe one obtained in Examples 11 and 12 above.

Example 14 To a stirred solution of 25 g. of N-methylanthranilic acidmethyl ester in 100 ml. of dimethylforrnamide at 0, 35 g. ofa-bromopropionyl bromide was added and stirring continued for 2-1ours.The reaction mixture was diluted with 1000 ml. of methanol and thensaturated with ammonia. After 4 days at room temperature, thecrystallized part was filtered off, washed with methanol and dried. Itgave dl-l,3-dimethyl-3H-1,4-benzodiazepin-2,5(1H,4H)-dione, M.P.253.5255.

In the same manner, but using methylamine instead of ammonia andrecrystallizing the product from acetone, there was obtaineddl-1,3,4-trimethyl-3H-1,4-benzodiazepin-2,5(1H,4H)-dione, M.P. 137-139".

Example 15 To a stirred solution of g. of N-benzylanthranilic acidmethyl ester in 100 ml. dimethylformamide at 0 was added 40 g. ofa-bromopropionyl bromide and stirring continued for 2 hours. Thereaction mixture was diluted with water, and the resulting suspensionextracted with methylene chloride. The extract was washed with water,dried over anhydrous sodium sulfate and evaporated. The residue wascrystallized from acetone-hexane, givingN-benzyl-N-(a-brompopropionyl)anthranilic acid methyl ester, M.P.73-75".

A solution of 11.3 g. of N-benzyl-N-(a-bromopropionyl)anthranilic acidmethyl ester in 1000 ml. of methancl was saturated with ammonia and leftat room temperature for 24 hours. It was then diluted with a largeexcess of water and the resulting suspension extracted with methylenechloride. The extract was washed with water, dried and evaporated. Theresidue was chromatographed on an alumina column. The fractions elutedwith 25% ethyl acetate in benzene were evaporated and the residuecrystallized from acetone-ether. It gave dl-1-benzyl-3- methyl-3H1,4-benzodiazepin 2,5(1H,4H) dione, M.P. 209-213 Example 16 Example 17 vA solution of .7 g. of N-benzyl-N=(a-bromopropionyl) anthranilic acidmethyl ester in 1000 ml. of methanol was saturated at 60 withmethylamine and left 72 hours at room temperature. It was thenevaporated, water was added to the residue and the resulting mixtureextracted with methylene chloride. The extract was washed with water,dried and evaporated. The residue was crystallized from ether, givingdl-1-benzyl-3,4-dimethyl- 3H-1,4 benzodiazepin 2,5(1H, 4H) dione, M.P.137139.5.

Example 18 To a solution of 5.6 g. of dl-1-benzyl-3-methyl-3H-1,4-benzodiazepin-2,5-(1H,4H)-dione in 300 ml. of glacial acetic acid,0.5 g. of 10% palladium on carbon catalyst was added and the suspensionhydrogenated at 60 and 1000 p.s.i. for 1 week. After filtration andevaporation, the crystalline residue was chromatographed on an aluminacolumn. The fractions eluted with 10% ethyl, acetate in benzene wereevaporated, and the residue, recrystallized from acetone-ether, gavedl-l-cyclohexylmethyl 3 methyl 1,4 benzodiazepin 2,5(1H,4H)- dione, M.P.184-186".

The fractions eluted with 5% methanol in benzene were evaporated, andthe residue recrystallized from methanol, yieldingdl-3-methyl-3H-1,4-benzodiazepin-2,5 (lH,4H)-dione, M.P. 320.5-321.

Example 19 The sirupy N-oenzyl-N-bromoacetylanthranilic acid methylester, obtained from 8 g. N-benzylanthranilic acid methyl esteraccording to the procedure of Example 7 above, was dissolved in 500 ml.of methanol. To this solution was added 6 g. of n-butylamine, and theresulting mixture was boiled for 7 hours, then evaporated. Water wasadded to the residue and extracted with methylene chloride. The extractwas washed with water, dried and evaporated. The oily residue waschromato- 7 graphed on an alumina column. The fractions eluted with 80%benzene-% hexane gave, after crystallization from ether-hexane,1-benzyl-4-butyl-3H-1,4-benzodiazepin-2,5(1H,4H)-dione, M.P. 1l3-l1-6.5.

Example 20 Proceeding from 5-chloro-N-methylanthranilic acid methylester and using the procedures of Examples 1 and 2 above,7-chloro-l-methyl-3H-l,4-benzodiazepine-2,5 (1H,4H)-dione was prepared.Upon crystallization from methylene chloride-ether it melted at1715-1735".

Example 21 Proceeding from S-chloroanthranilic acid and using theprocedure of Example 13 above, 7-chloro-4-methyl-3H-l,4-benzodiazepine-2,5(1H,4H)-dione was prepared. Upon crystallizationfrom acetone-ether it melted at 253-255.

Example 22 Proceeding from 5-chloro-N-methylanthranilic acid methylester and using the procedure of Examples 1 and 3 above,7-chloro-1,4-dimethyl-3H-1,4-benzodiazepine- 2,5 (1H,4H)-dione wasprepared. Upon crystallization from acetone-ether it melted at 182-1835Example 23 Proceeding from 4-chloro-N-methylanthranilic acid methylester and using the procedure of Examples 1 and 2 above,8-chloro-l-methyl-3H-l,4-benzodiazepine-2,5 (lH,4H)-dione was prepared.Upon crystallization from acetone-ether it melted at 2l0-2l1.5.

Example 24 Proceeding from 4-chloro-N-methylanthranilic acid methylester and using the procedure of Examples 1 and 3 above,S-chloro-l,4-dimethyl-3H-1,4-benzodiazepine- 2,5(lH,4H)-dione wasprepared. Upon crystallization from acetone-ether it melted at 198-200".

Example 25 Proceeding from 5-chloro-N-benzylanthranilic acid methylester and using the procedure of Examples 1 and 2 above,7-chloro-1-benzyl-3H1,4-benzodiazepine-2,5 (lH,4H)-dione was prepared.Upon crystallization from acetone-ether is melted at 202-203".

Example 26 Proceeding from N-(p-nitrobenzyl)-anthranilic acid methylester and using the procedure of Examples 1 and 2 above,l-(p-nitrobenzyl)-3H-1,4-benzodiazepine-2,5. (1H,4H)-dione was prepared.Upon crystallization from methanol it melted at 262-264.

Example 27 Proceeding from N-(p-nitrobenzyl)-anthranilic acid methylester and using the procedure of Examples 1 and 3 above, 1(p-nitrobenzyl)-4 methyl 3H 1,4 benzodiazepine-2,5 (1H,4H)-dione wasprepared. Upon crystallization from methanol it melted at 199200.

Example 28 To a suspension of 2 g. of lithium aluminum hydride in 400ml. of absolute tetrahydrofuran, 2 g. of 3H-l,4-benzodiazepine-2,5(lH,4H)-dione was added at 0. The

reaction mixture turned green, and was refluxed for l hour. Slowaddition of saturated aqueous sodium sulfate at 0 decomposed the excessof reagent and the complex of products, and when a clear solution wasobtained, anhydrous sodium sulfate was added and the solution filteredoff. After evaporation, methanol was added to the sirupy residue, aminor precipitate was filtered oil, and the crystals were recrystallizedfrom methanol, giving lH-2,3-dihydro-l,4-benzodiazepine, M.P. 244-246.

The evaporation of the methanolic mother liquors gave sirupy1H-2,3,4,5-tetrahydro-1,4-benzodiazepine. It was dissolved in 10 ml. ofmethanol and ether saturated with hydrochloric acid was added causingprecipitation of 1H- 2,3,4,5 tetrahydro 1,4 benzodiazepinedihydrochloride, M.P. 243-244, after recrystallization frommethanolacetone.

We claim:

1. A compound selected from the group consisting of a compound of theformula:

and acid addition salts thereof; wherein R is selected from the groupconsisting of lower, alkyl, phenyl-lower alkyl, nitrophenyl-lower alkyl,hydrogen and cyclo-lower alkyl-lower alkyl; R is selected from the groupconsisting of hydrogen and lower alkyl; and R is selected from the groupconsisting of hydrogen and halogen.

2. A compound selected from the group consisting of a compound of theformula:

No references cited.

NICHOLAS S. RIZZO, Primary Examiner.

ALTON D. ROLLINS, Assistant Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THEFORMULA:
 2. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUNDOF THE FORMULA: